Transcriptional regulation of neural development and degeneration

Abstract

The architecture and functional interactions of the cerebral cortex are fascinating in their complexity of billions of neurons and glial cells connected in intricate circuitries and spatial regions. During development, transcription factors and chromatin modifiers work together to coordinate gene expression programs that drive the formation of the cerebral cortex. Notably, neurological aberrations can arise when perturbation occurs in these tightly regulated programs. Although our understanding of corticogenesis has advanced with the identification of master regulators of neural development, we only have rudimentary knowledge of the molecular mechanisms these factors use to execute the developmental programs.

The aim of this thesis is to investigate the transcriptional mechanisms of gene regulation by key transcription factors involved in telencephalic development and disease, using primarily human neural progenitors as an in vitro model of development.

Study I reports a novel mechanism through an interaction between the co-repressor NCOR and the transcription factor FOXP2. Genome-wide mapping of common binding sites of NCOR/FOXP2 in human iPS-derived neural progenitors included two putative regulatory elements in the proximity of the SLITRK gene cluster. Chromosome conformation capture (3C) confirmed the interaction between the SLITRK cluster gene promoters and the regulatory elements where FOXP2/NCOR binds, which proposes a possible role for this regulatory mechanism in accurate development and possibly evolution of vocal and motor skills. Study II demonstrates that the transcription factor PAX6 can function as a repressor and recruit the histone demethylase KDM5C to repress a subset of genes involved in Notch signaling, which is critical for several neuronal functions, proposing that neurodevelopmental aberrations by PAX6 and/or KDM5C mutations maybe be associated with defects in Notch signaling. Study III explores the gene regulation effects on pluripotency mediated by different handling techniques of human embryonic stem cells and human induced pluripotent stem cells, and shows that reversible gene expression changes indeed occur during prolonged culture in enzymatic conditions. Study IV reveals that a single nucleotide polymorphism (SNP) in the promoter of the HTT gene, responsible for Huntington’s disease, disrupts the NF-κB binding and transcriptional regulation of the HTT gene, indicating that silencing of the HTT gene is a promising therapeutic strategy in Huntington’s disease.

Taken together, the work of this thesis strengthens the hypothesis that the interplay between transcription factors and chromatin structure is critical for maintaining neurological fitness.